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Level of unique T cell clonotypes is associated with clonal hematopoiesis and survival in patients with lymphoma undergoing ASCT

Bone Marrow Transplantation volume 57, pages 674–677 (2022)Cite this article

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The adaptive immune system, and especially the role of T cells, has become a key focus in the treatment of lymphoma. The T cell receptor (TCR) is exclusive for every T cell clone and thus provides unique information on the condition of the immune system. Novel NGS sequencing has made it possible to identify hundred thousands of T cell clones in a single blood sample, consequently termed the TCR repertoire. Poorer diversity of the systemic TCR repertoire has been associated with inferior outcomes in solid cancers [1]. Previous studies in lymphoma have only investigated patients receiving experimental therapies or used simple PCR-based methods enabling only analysis of few circulating T cell clones per patient [2]. Neither the biological diversity of the systemic T cell clones nor the level of circulating T cell clonotypes have been examined in relation to clinical outcomes after autologous stem cell transplant (ASCT). These features of the inherent T cell composition might also be of relevance to novel T cell engaging lymphoma therapies, such as CAR T cell therapy [3] and bispecific (CD20×CD3) antibodies [4], as both employ the patients’ inherent immune system.

In this study, we explored pre-transplant systemic T cell diversity and clonotypes in patients with lymphoma undergoing high-dose chemotherapy and ASCT. We have analyzed how these T cell variables correlate with patient characteristics, clonal hematopoiesis and long-term survival. Previous studies have shown that mobilized peripheral stem cell harvest products are enriched with T cells [5]. Autologous peripheral blood stem cell harvest samples from patients with lymphoma (predominantly B cell Non-Hodgkin lymphoma) were collected as part of a national population-based cohort study [6]. All samples were purified for RNA with the Qiagen Allprep DNA/RNA kit. Only samples with RNA integrity number (RIN; BioAnalyzer determined) value above 6.5 were used for further analysis. Sequencing libraries were prepared with the Illumina Immune Repertoire panel and sequenced on an Illumina NextSeq with a 2 × 150 bp paired-end kit. Samples with very low level of aligned TCR reads implicated poor starting material in the peripheral stem cell graft or sample preparation failure. To ensure optimal quality for TCR repertoire analyses, samples with less than 100,000 aligned reads of the TCR β chain were excluded. We performed high-throughput RNA-based sequencing of the V, D, and J segment of the TCR β-chain to identify unique rearrangements. Using the MiXCR bioinformatic pipeline [7] we analyzed the number of unique clonotypes and diversity of the TCR repertoire, as calculated by the Simpson index [8]. Clonotype and diversity were for categorical analyses split in two groups by the median, respectively. As previously described [6], patient data was obtained from five nation-wide registries encompassing comprehensive clinical data. Data included diagnoses, age, stage, oncological treatment, survival, hospital admissions, discharge diagnoses, and histological examinations. Additionally, electronic and paper patient records were manually assessed for quality control and in cases with missing information. The study was approved by the Capital Region ethical committee on behalf all regions in Denmark.

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Fig. 1: Correlation of patient age and T cell features.
Fig. 2: Association of systemic T cell characteristics with baseline variables and survival.

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Acknowledgements

The authors wish to thank all participating centres and technical staff. SH and GØJ are funded by scholarships from Rigshospitalet’s Research Fund. Reagents were supported by supported by a grant from Region Hovedstadens’ Research Foundation. This study was furthermore supported by grants from The Denmark-America Fund, Dagmar Marshalls Fund, The Danish Cancer Society, Reinholdt W. Jorks Fund, A.P. Møller Fund (Lægefonden), Sejer Persson & Lis Klüwer Persson’s Fund. SH and KG are also funded by the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant NNF17CC0027852). The project is part of the Danish Research Center for Precision Medicine in Blood Cancers funded by the Danish Cancer Society grant no. R223-A13071.

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Author notes

  1. These authors contributed equally: Simon Husby, Gustav Ø Jørgensen.

Authors and Affiliations

  1. Department of Hematology, Rigshospitalet, Copenhagen, Denmark

    Simon Husby, Gustav Ø. Jørgensen, Pär Josefsson, Peter Brown & Kirsten Grønbæk

  2. Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark

    Simon Husby, Gustav Ø. Jørgensen, Francesco Favero, Jakob Schmidt Jespersen, Francisco G. Rodriguez-Gonzalez, Joachim Weischenfeldt & Kirsten Grønbæk

  3. Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Simon Husby, Jakob Schmidt Jespersen & Kirsten Grønbæk

  4. Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark

    Francesco Favero, Francisco G. Rodriguez-Gonzalez & Joachim Weischenfeldt

  5. Department of Clinical Immunology, Odense University Hospital, Odense, Denmark

    Christian Nielsen

  6. Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Odense University Hospital, Odense, Denmark

    Christian Nielsen & Thomas Stauffer Larsen

  7. Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark

    Betina Sorensen

  8. Department of Hematology, Aarhus University Hospital, Aarhus, Denmark

    Lene H. Ebbesen & Michael Thorsgaard

  9. Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark

    John Bæch

  10. Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark

    Eva K. Haastrup

  11. Department of Hematology, Aalborg University Hospital, Aalborg, Denmark

    Tarec C. El-Galaly

  12. Department of Hematology, Odense University Hospital, Odense, Denmark

    Thomas Stauffer Larsen

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Contributions

SH, GØJ, and KG conceived the study, CN, BS, LHE, JB, EKH provided patient samples, SH, PJ, MT, TCE, PB, TSL provided clinical data, GØJ, SH, FGR-G, JSJ performed the analyses, SH, GØJ, FF, TSL, JW, KG analyzed the data, SH, GØJ wrote the manuscript; and all authors participated in interpretation of data, manuscript writing, and review of the manuscript.

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Correspondence to Simon Husby.

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Husby, S., Jørgensen, G.Ø., Favero, F. et al. Level of unique T cell clonotypes is associated with clonal hematopoiesis and survival in patients with lymphoma undergoing ASCT. Bone Marrow Transplant 57, 674–677 (2022). https://doi.org/10.1038/s41409-022-01580-2

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